The development of animal models mimicking painful peripheral neuropathies in humans offers an important and much needed opportunity to investigate underlying mechanisms, with the expectation that this will lead to improved clinical treatment for humans. Our hypothesis, which is held by many, is that NMDA receptor activation is an important mechanism contributing to the generation and maintenance of neuropathic pain. Although this hypothesis is based on several different lines of evidence, it has not been rigorously tested. Much of the evidence is derived from acute pharmacological studies in which the effect of an NMDA antagonist in measured on a single phenomenon (i.e. heat hyperalgesia). It is unknown whether NMDA antagonists will also attenuate the common symptoms of mechanical and cold allodynia. Furthermore, the physiological and anatomical correlates of this treatment are largely unknown, thus we can only speculate as to how this treatment effects the spinal cord at a cellular and neurochemical level. The present proposal carefully investigates NMDA receptor involvement in neuropathic pain in a rat and primate model of neuropathy. The studies will document the behavioral, electrophysiological and anatomical changes that follow chronic intraperitoneal (IP) and intrathecal (IT) treatment with the non- competitive NMDA receptor antagonists Memantine, Dextrorphan and Ketamine. All of these drugs are currently used in humans for the treatment of other ailments. The basic hypothesis is that NMDA receptor activation plays a critical role in neuropathic pain. Testing this hypothesis using behavioral paradigms, studies will demonstrate that the non-competitive NMDA antagonists delivered IP or IT, will effectively attenuate the symptoms of mechanical and cold allodynia and heat hyperalgesia in a rat and primate model of peripheral neuropathy. Testing this hypothesis using electrophysiological studies, we will demonstrate that chronic IP or IT treatment with NMDA antagonists will prevent the central sensitization of STT cells observed in neuropathic primates. Testing this hypothesis using anatomical methods, studies will demonstrate changes in immunostaining densities for those substances related to NMDA-receptor activation and/or modulation. In a time course study, changes in DH staining densities of glutamate, glutamate-receptor, substance P, SP-receptor, glycine, glycine- receptor, nitric oxide, and protein kinase C will be correlated with changes in behavior. It is anticipated that drug treatment will reverse or block these anatomical changes. This proposal extends our previous work with neuropathy models by initiating new studies documenting the potential use of NMDA antagonists for treatment of neuropathic pain. The combined studies will provide a global view of changes in CNS sensory processing following treatment with these drugs. The results will elucidate mechanisms of neuropathic pain and determine whether NMDA antagonists will provide a needed therapeutic tool for a clinical phenomenon historically very difficult to treat.